The previous Principal Investigator of this study, Dr. Roger R. Williams, was killed in the Swissair airplane crash last year. He has been replaced as Principal Investigator in this multicenter study by Paul N. Hopkins, M.D., M.S.P.H. The Principal Investigator for the overall project is Dr. Gordon Williams at Brigham and Women's Hospital, Harvard Medical School, Boston. This project addresses the hypothesis that mutations at selected candidate genetic loci contribute to the development of essential hypertension and/or an intermediate phenotype of essential hypertension. The hypothesis is tested using the affected sibling pair method. The intermediate phenotypes to be determined include modulation status, salt sensitivity, renin status, kallikrein excretion, and red cell ion flux. This is a collaborative effort at three sites, Salt Lake City, Boston, and Paris. Approximately 100 sibling pairs with early-onset hypertension will be studied at each site. Early results indicate that the angiotensinogen gene (AGT) is linked to human essential hypertension. Furthermore, a common variant of AGT (M235T) is associated with hypertension, and this variant is present with a gene frequency of about 35% in the general population. Recent studies have addressed the effect of the AGT genotype on renal and adrenal responses to angiotensin II infusions in hypertensive sibling pairs. A significant trend for increased prevalence of non-modulation was found among those with a T235 genotype. Other analyses have shown increasing risk of non-modulation of both AGT T235 and ACE D genotypes at present. Data analysis has also demonstrated a strong concordance of low-renin hypertension within sibling pairs. Although many results from these studies have been published, the latter findings are now being prepared for submission.